T315I CLONE SELECTION IN A PHI+ ALL PATIENT UNDER MAINTENANCE PONATINIB
Author(s): ,
Jasmine Noetzli
Affiliations:
Hematology,CHUV,Lausanne,Switzerland
,
Mathilde Gavillet
Affiliations:
Hematology,CHUV,Lausanne,Switzerland
,
Stavroula Masouridi-Levrat
Affiliations:
Hematology,HUG,Geneva,Switzerland
,
Anna Priovolos Hughes
Affiliations:
Hematology,CHUV,Lausanne,Switzerland
,
Claire Abbal
Affiliations:
LCH,CHUV,Lausanne,Switzerland
Olivier Spertini
Affiliations:
Hematology,CHUV,Lausanne,Switzerland
EHA Library. Noetzli J. Jun 12, 2015; 102942; PB1620 Disclosure(s): CHUV
Hematology
Jasmine Noetzli
Jasmine Noetzli
Contributions
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Abstract
Abstract: PB1620

Type: Publication Only

Background

Ponatinib is a third generation tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with T315I or resistant/intolerant to other TKIs. Serious vascular adverse events have been reported at the dosage of 45 mg once daily suggesting that a reduction in the dosage of ponatinib may be advisable.



Aims

We present here the case of a Ph+ ALL in 2nd relapse who achieved a molecular remission with ponatinib 30 mg/day. To decrease the risk of vascular complications, ponatinib dosage was reduced to 15 mg/day during maintenance therapy. We examined whether this ponatinib dosage is sufficient to prevent molecular relapse.



Methods

Residual disease was measured by RQ-PCR and BCR-ABL mutations were detected by Sanger sequencing. 



Results

This 39-year-old patient was diagnosed in 2008 with a Ph+ ALL (Figure 1). He was first treated with imatinib (GRAALL/GRAAPH 2005 trial) and then successively with dasatinib, nilotinib and bosutinib because of intolerance or resistance and finally with ponatinib. Due to liver toxicity, ponatinib was given at 30 mg/day as maintenance therapy. One year after the second transplant, while the patient was still in CR, an unexpected high rate of ponatinib-induced vascular events was reported. According to recommendations made for CML in major molecular response, the maintenance therapy was reduced to 15 mg/day.

Six months later, a molecular relapse was identified in bone marrow and Sanger sequencing revealed a T315I mutation in BCR-ABL kinase domain (KD). The patient was treated with steroids, a single dose of vincristine (1,4mg/m2) and ponatinib 45mg once daily. Fifteen days later, MBCR-ABL level was reduced by 1 log and sequencing showed the concomitant presence of wild-type and T315I BCR-ABL KD. Donor lymphocyte infusions were started. Three months later, the MBCR-ABL/ABL ratio was 0,025%. Presently, 6 months after the 2nd relapse, the patient is in complete molecular remission, without graft versus host disease.

 



Summary

We report here the clinical course of a Ph+ ALL patient who was treated with ponatinib 15mg/day, as maintenance therapy, and developed a BCR-ABL T315I mutation leading to leukemia molecular relapse. This clonal evolution was reversed, without adverse effects, by increasing ponatinib dosage to 45mg/day suggesting that ponatinib dose reduction may not be appropriate in Ph+ALL maintenance therapy. 



Keyword(s): Acute lymphoblastic leukemia, BCR-ABL, Maintenance, Tyrosine kinase inhibitor



Session topic: Publication Only

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